Malaria, caused by four Plasmodium species transmitted between humans and Anopheles mosquitoes, continues to be a major global public health problem. Annually, more than 300-400 million people worldwide develop malaria; each year, malaria kills ~800,000, primarily due to P. falciparum infecting children in sub-Saharan Africa. There is no highly effective, deployable malaria vaccine, and the prevalence of drug-resistant malaria is increasing throughout Africa, Asia and South America, which has been associated with an increase in morbidity and mortality. Even chloroquine-resistant P. vivax is emerging as a public health problem, mostly in Oceania but occasional cases have been reported elsewhere including in Peru. Alternative strategies for preventing and reducing the human burden of malaria are imperative. A major challenge confronting the malaria field is how to apply advanced genomics-based knowledge towards the amelioration of malaria at both the field level and in the real world setting. This project will take such an approach towards understanding mechanisms of naturally acquired anti-malarial immunity in a low-transmission setting, lessons that may be generalizable to other regions. The major hypothesis to be testing in this project is that asymptomatic parasitemia reflects clinical immunity to which complex interactions of antibody, memory B cells and helper CD4+ T cells contribute. Prior human studies clearly indicate that specific antibodies can mediate at least a reduction in parasitemia, and hence contribute to clinical immunity. This hypothesis will be tested in three Specific Aims: 1, To determine differential antibody responses of symptomatic vs. asymptomatic Plasmodium vivax malaria patients to asexual blood stage antigens; 2, To quantify antigen-specific B cell and compare memory B cell phenotypes in symptomatic vs. asymptomatic P. vivax malaria patients; and 3, To compare and quantify antigen-specific CD4+ T cell responses in symptomatic vs. asymptomatic P. vivax malaria patients. This project, to investigate the human immune responses of symptomatic and asymptomatic patients with P. vivax malaria in the Peruvian Amazon, will be carried out in conjunction with individuals at UC San Diego, La Jolla Institute of Allergy and Immunology, UC Irvine, and Universidad Peruana Cayetano Heredia. This project will provide the intensive career development experience that will enable me to obtain state-of-the-art, multidisciplinary training in malaria immunology, with guidance from an internationally-renowned group of mentors with varying and complementary expertise. The implications of this study will extend to P. falciparum and to malaria immunity studies in multiple different contexts of malaria epidemiology and transmission, and provide the basis to extend and continue such work towards more effective malaria vaccine development in the future (i.e. towards research career independent, new R01 grant, etc.) RELEVANCE: This project will allow us to learn more about how people become immune to malaria. Studying patients with malaria due to Plasmodium vivax in the Amazon of Peru, we will compare people who have become immune to malaria after natural infection to people who are not immune. The results of this study will allow us to better design a vaccine to prevent and perhaps treat malaria.